DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Amendments
2. The amendments filed March 11, 2026 have been entered. Claims 1-129, 133-134, 139-143, and 145-153 were cancelled. Claim 130 has been amended.
Claims 130-132, 135-138, 144 and 154-155 are under consideration in this Office Action.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on March 11, 2026 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Claim Objections and Rejections
4. The rejection of claims 130-136 and 154-155 under 35 U.S.C. 103 as being unpatentable over Ella et al., in view of Konadu et al., is withdrawn in view of Applicants amendments, arguments and declaration.
5. The rejection of claims 137-138 under 35 U.S.C. 103 as being unpatentable over Ella et al., in view of Konadu et al. and further in view of Levine et al., is withdrawn in view of Applicants amendments, arguments and declaration.
New Grounds of Rejection Necessitated By Applicants Amendments
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
6. Claims 130-132, 135-136, 144 and 154-155 are rejected under 35 U.S.C. 103 as being unpatentable over CN102935226 (published 2013-02-20; priority to 2012-11-16) in view of Ali et al., (Hum Vaccin Immunother. 2014;10(6):1494-8. Epub 2014 Mar 6) and Ella et al., (WO 2020095324 published May 2020; priority to Nov 10, 2018).
The claims are drawn to an immunogenic composition comprising: a) 1.25 mg to 50mg of a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) 1.25 mg to 50mg of a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) diphtheria toxoid (DT) conjugate antigen wherein the DT is derivatized with an adipic acid dihydrazide (ADH) linker before conjugation with the Salmonella enterica serovar paratyphi A OSP polysaccharide.
CN102935226 teach a typhoid fever and paratyphoid fever combined vaccine. The typhoid fever and paratyphoid fever combined vaccine comprises typhoid Vi polysaccharide and paratyphoid fever thallus specific polysaccharide O-SP [abstract]. Animal experiments prove that the typhoid fever and paratyphoid fever combined vaccine can induce high-level anti-typhoid Vi polysaccharide and anti-paratyphoid fever lipopolysaccharide (LPS) antibody, has immunologic memory reaction, and has no acute toxicity reactions [abstract]. The Salmonella typhoid Vi-TT and paratyphoid A O-SP-TT conjugate mix the combined vaccine of making, use typhoid Vi polysaccharide and paratyphoid A O-specific polysaccharide (O-SP), two kinds of polysaccharide are single polysaccharide, can well control the impurity such as albumen and nucleic acid, and perfect quality standard is arranged [Summary of Invention]. Preferably, every person-portion typhoid fever paratyphoid A combined vaccine all is not less than 10ug containing typhoid fever thalline capsular polysaccharide and paratyphoid A thalline specific polysaccharide O-SP. Every person-portion all is not less than 10ug containing typhoid Vi polysaccharide, paratyphoid A O-SP polysaccharide [Embodiment 5]. The dilution of finished product vaccine is respectively to 5ug/ml for 10ug/ml(containing typhoid Vi polysaccharide and paratyphoid A O-SP polysaccharide) [potency test]. Thus teaching the instantly claimed 1.25 mg to 50mg amount of Salmonella enterica serovar typhi Vi polysaccharide and a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP). CN102935226 prepared typhoid Vi polysaccharide-carrier protein conjugate: the derivation carrier protein to obtain a typhoid Vi polysaccharide-carrier protein conjugate and preparing paratyphoid A thalline specific polysaccharide O-SP-carrier protein conjugate: with adipic dihydrazide and paratyphoid A thalline specific polysaccharide O-SP, carry out coupled reaction, make the O-SP-AH derivant, [Summary of Invention]. Embodiment 3 teach the carrier protein of tetanus toxoid (TT) as typhoid Vi polysaccharide. Embodiment 3 teach carrier protein derivation with adipic dihydrazide (ADH), adding carbodiimide (EDAC) to make the ratio of EDAC and albumen. Embodiment 4 teach the preparation method of O-SP-carrier protein conjugate O-SP-ADH (adipic dihydrazide (AH) using the derivatized carrier protein. Embodiment 5 teach the conjugate stock solution are added to aseptic apyrogeneity water for injection dilution after mixing, add appropriate sugar as the excipient [embodiment 5].
Therefore, CN102935226 teach an immunogenic composition comprising: a) 1.25 mg to 50mg of a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) 1.25 mg to 50mg of a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) toxoid carrier conjugate antigen wherein the carrier is derivatized with an adipic acid dihydrazide (ADH) linker before conjugation with the Salmonella enterica serovar paratyphi A OSP polysaccharide. However CN102935226 does not teach the carrier toxoid for Salmonella enterica serovar paratyphi A OSP polysaccharide is diphtheria.
Ali et al., teach Salmonella enterica serovar Paratyphi A O-specific polysaccharide conjugated to diphtheria toxoid. Ali et al., teach Salmonella enterica serovar Paratyphi A (S. Paratyphi A) is a human restricted pathogen that can cause systemic infection (paratyphoid fever) with recently increased incidence particularly in developing countries. Currently there is no licensed vaccine for prevention of infection from S. Paratyphi A. In this study the O-specific polysaccharide (OSP) of S. Paratyphi A was conjugated to diphtheria toxoid (DT) with and without adipic acid dihydrazide (AH) as a linker [abstract]. Binding of the OSP to a carrier protein was intended to convert a T-cell independent OSP response to a T-cell dependent response inducing higher levels of anti-OSP antibodies and immunological memory. These conjugates (OSP-AH-DT and OSP-DT) were evaluated for their immunogenicity in mice. The S. Paratyphi A OSP-DT conjugate induced a poor anti-OSP response less than that observed with LPS while the OSP-AH-DT conjugate induced a significantly higher antibody titer compared with LPS alone. The study also demonstrated diphtheria toxoid as a potential carrier protein for conjugate vaccine candidates using S. Paratyphi A OSP [abstract]. Conjugation of a polysaccharide antigen to a carrier protein results in a T-cell dependent immune response characterized by higher titers of anti-polysaccharide antibodies having bactericidal activity and induction of memory cells. This conjugation can be achieved by using an intermediate linker molecule such as adipic acid dihydrazide (ADH). S. Paratyphi A OSP-protein conjugates were previously shown to be safe and to elicit anti-OSP IgG antibodies in all age groups [Introduction].
Various conjugation strategies have been reported including recent conjugation chemistry to link the S. Paratyphi A O:2 and the carrier protein CRM197, using the terminus 3-deoxy-D-manno-octulosonic acid (KDO), thus leaving the O:2 chain unmodified. These new conjugates were found to have bactericidal activity against S. Paratyphi A [Discussion]. Conjugation of S. Paratyphi A OSP with diphtheria toxoid (DT) has not been previously reported. We have conjugated OSP of S. Paratyphi A with DT and evaluated immunogenicity in mice. Two conjugates of S. Paratyphi A OSP were prepared with DT: one using an ADH linker molecule and the other directly linking OSP to DT. The conjugate with the linker showed a significantly higher anti-OSP response compared with LPS alone whereas the conjugate prepared by directly linking OSP to DT was poorly immunogenic. Ali et al., teach the OSP-AH-DT and OSP-DT conjugate permits better access to the antigen sites on the OSP in the conjugate with the spacer and/or allow for higher free polysaccharide content in the conjugate. Ali et al., teach various conjugation strategies have been reported including recent conjugation chemistry to link the S. Paratyphi A O:2 and the carrier protein CRM197. These conjugates were found to have bactericidal activity against S. Paratyphi A [Discussion].
Ali states S. Paratyphi A OSP was bound to tetanus toxoid (TT) with and without ADH linker, and the conjugate with the linker was more immunogenic than the conjugate without the linker. However, that conjugate did not elicit a booster response in young children. This was in contrast to the booster response elicited in this age group by pneumococcus type 6B-TT, Vi-rEPA, and Shigella flexneri 2a-rEPA conjugate [Discussion]. The results presented here demonstrated that OSP purified from S. Paratyphi A can be conjugated to DT carrier protein. The enhanced immune response seen with the OSP-AH-DT conjugate is indicative of a successful conjugation and warrants further development as a vaccine candidate [Discussion].
Ella et al., teach multivalent conjugate compositions against Salmonella diseases along with combined vaccine composition of glycol-conjugates in bivalent combinations [abstract]. The immunogenic composition comprise two or more of an antigen of Salmonella enteritidis, an antigen of Salmonella typhimurium, an antigen of Salmonella typhi; and/or an antigen of Salmonella paratyphi, wherein each antigen is conjugated to one or more carrier molecules. The typhoid Vi polysaccharide is covalently conjugated on the carrier protein to form conjugative vaccine that can be used to generate active immunity in humans and other mammals, and for preventing typhoid infection. After the typhoid Vi polysaccharide is conjugated with protein, the recognition mode of organism to typhoid Vi antigen is changed into T cell depended antigen that can be used for immunity of all people and possesses obvious effect for boosting immunity [para 12]. Ella et al., teach stable conjugate vaccine formulations for protections against Salmonella typhii, and methods of conjugation between Vi-polysaccharide of S. typhii to tetanus toxoid as the carrier protein, responsible for producing improved T-dependent immune response against Typhoid fever caused by Salmonella typhi [para 15]. The immunogenic composition, wherein the one or more carrier molecules comprises one or more of tetanus toxin, tetanus toxin heavy chain proteins, diphtheria toxoid, tetanus toxoid, Escherichia coli heat-labile toxin B subunit, Neisseria meningitidis outer membrane complex, and modifications thereof [para 27]. Thus teaching claim 144. One embodiment of the invention comprises S. typhi Vi conjugated by carbodiimide mediated modification of S. typhi Vi polysaccharide with adipic acid dihydrazide (ADH) that introduces reactive hydrazide groups that are then used to link to tetanus toxoid (TT) via a second carbodiimide step [para 81]. Thus teaching claim 130 in part. Table 1 teach a bivalent vaccine composition comprising a bivalent conjugate vaccine containing Salmonella typhi Vi conjugate and Salmonella paratyphi A conjugate (Single dose) 5-30ug each/dose, PBS with tween 80.
The immunogenic composition comprises a pharmaceutically acceptable buffer such as PBS and Tween 80 [para 28]. It is noted that Tween 80 is also generically known as polysorbate 80, thereby teaching claim 136. The immunogenic composition comprises a stabilizer such as 2-phenoxy ethanol [para 29]. Thus teaching claim 131. The immunogenic composition comprises an adjuvant [para 30]. Adjuvants include, but are not limited to analgesic adjuvants, inorganic compounds such as alum, aluminum hydroxide, aluminum phosphate and others [para 72]. Thus teaching claim 132. Each antigenic conjugate is present in the immunogenic composition at a dose range of about 5 μg/dose to about 30 μg/dose [para 31]. Thus teaching claim 130. Stabilizing agents include, for example, pharmaceutically acceptable sugars [para 71]. The trivalent Salmonella conjugate vaccine drug product in multi-dose vials and the bivalent Salmonella conjugate vaccine drug product in both multi-dose and mono-dose vials were maintained in controlled storage at 2-8° C. with stability being monitored only for the Vi conjugate component [para 118]. Real-time stability testing was carried for evaluating the stability of vaccine compositions according to embodiments of the invention at recommended storage conditions of 2-8° C [See example 7]. Thus, compositions according to embodiments of the invention were found to be stable at recommended storage conditions of 2-8° C [para 157]. It is noted that neither claim 154 nor 155 include any additional components. Thus Ella et al., teach claims 154-155.
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Ali’s Salmonella enterica serovar paratyphi A O-specific polysaccharide (O-SP) conjugated to diphtheria toxoid and Ella et al., Salmonella enterica serovar typhi Vi polysaccharide conjugated to tetanus when CN102935226 clearly teach an immunogenic composition comprising:1.25 mg to 50mg of a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) 1.25 mg to 50mg of a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) toxoid carrier conjugate antigen in order to treat typhoid and paratyphoid fever using a combined vaccine. One of ordinary skill in the art would have a reasonable expectation of success by incorporating the independent conjugates because CN102935226 teach the combination composition can produce the immune response identical with independent conjugates. Ali et al., teach S. Paratyphi A conjugated to diphtheria toxoid (DT) with adipic acid dihydrazide (AH) as a linker induces higher levels of anti-OSP antibodies and immunological memory; thus no more than routine skill is required to exchange carrier proteins. Furthermore when using the ADH linked DT, the conjugate produced higher titers of anti-polysaccharide antibodies having bactericidal activity and induced memory cells. Additionally, no more than routine skill would have been required to incorporate the conjugate antigen when Ella et al., already teach a bivalent immunogenic composition comprising a conjugate vaccine containing Salmonella typhi Vi tetanus conjugate and Salmonella paratyphi A conjugate. Finally, it would have been prima facie obvious to combine the invention of Ali and
Ella et al., already taught by CN102935226 to advantageously achieve an immunogenic composition against pathogenic S. enterica serovars Typhi and Paratyphi known to cause infections and fevers.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take an immunogenic composition, where there is no change in the respective function of the conjugates, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claim Rejections - 35 USC § 103
7. Claims 137-138 are rejected under 35 U.S.C. 103 as being unpatentable over
CN102935226 (published 2013-02-20; priority to 2012-11-16) in view of Ali et al., (Hum Vaccin Immunother. 2014;10(6):1494-8. Epub 2014 Mar 6) and Ella et al., (WO 2020095324 published May 2020; priority to Nov 10, 2018) as applied to claims 130-132, 135-136, 144 and 154-155 above, and further in view of Levine et al., (US 20130129776 published May 2013 priority to Nov 2011).
CN102935226, Ali et al., and Ella et al., teach an immunogenic composition comprising: a) 1.25 mg to 50mg of a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) 1.25 mg to 50mg of a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) diphtheria toxoid (DT) conjugate antigen wherein the DT is derivatized with an adipic acid dihydrazide (ADH) linker before conjugation with the Salmonella enterica serovar paratyphi A OSP polysaccharide. However, none specifically teach the inclusion of sucrose, sodium chloride and water as part of the composition.
Levine et al., teach multivalent Salmonella enterica serovar conjugate vaccines comprising conjugates including but not limited to S. Typhi, S. Paratyphi A wherein the conjugates comprise a hapten antigen and a carrier antigen, wherein at least one of the hapten antigens or carrier antigens is characteristic of the Salmonella enterica serovar. Such conjugate vaccines can be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, and the like [para 173]. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent. Suitable diluents include, for example, water, Ringer's solution and isotonic sodium chloride solution [para 174]. When in the form of solutions, suspensions and gels, in some embodiments, the formulations of the conjugates contain a major amount of water (preferably purified water) in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers, dispersing agents, buffering agents, preservatives, wetting agents, jelling agents, colors, and the like can also be present [para 177]. The isotonicity of the compositions can be attained using inorganic or organic solutes. Sodium chloride is particularly preferred. Buffering agents can be employed, such as acetic acid and salts, citric acid and salts, boric acid and salts, and phosphoric acid and salts [para 178]. Pharmaceutically acceptable carriers for pulmonary delivery of the conjugates include carbohydrates such as sucrose [para 182]. Formulations for dispensing from a powder inhaler device typically comprise a finely divided dry powder containing the conjugate, optionally including a bulking agent, such as sucrose [para 185]. Formulations suitable for use with a nebulizer, either jet or ultrasonic, typically comprise the conjugate dissolved or suspended in water at a concentration of about 0.01 or less to 100 mg or more of conjugate per mL of solution [para 183]. The multivalent conjugate vaccine Salmonella enterica serovars are administered to a subject as a pharmaceutical composition, which may contain salts, buffers, adjuvants, or other substances which are desirable for improving the efficacy of the composition. Adjuvants are substances that can be used to specifically augment a specific immune response. Mineral adjuvants include mineral salts (for example, AlK(SO4)2, AlNa(SO4)2, AlNH4 (SO4) [para 170]. A pharmaceutically acceptable preservative can be employed to increase the shelf life of the compositions. Benzyl alcohol can be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, or benzalkonium chloride can also be employed. A suitable concentration of the preservative can be from 0.02% to 2% based on the total weight although there can be appreciable variation depending upon the agent selected [para 180]. S. Paratyphi A is a serovar that, like S. Typhi, is human host restricted and has a similar pathogenesis and causes an identical clinical syndrome (enteric fever) in humans as S. Typhi [para 249].
Therefore, it would have been prima facie obvious at the time of applicants’ invention to apply Levine et al’s pharmaceutical components such as sucrose, sodium chloride, and water into CN102935226, Ali and Ella’s immunogenic composition comprising conjugated Salmonella enterica serovar paratyphi A and Salmonella enterica serovar in order to provide suitable formulations for improved efficacy of the composition. One of ordinary skill in the art would have a reasonable expectation of success by incorporating Levine’s ingredients to CN102935226, Ali and Ella’s conjugate composition because Levine teach the form of solutions where the formulations of the conjugates contain a major purified water in addition to the conjugate and minor amounts of other ingredients such as buffering agents and preservatives. Furthermore, no more than routine skill would have been required to incorporate the pharmaceutical ingredient of Levine et al., when Ella et al., already teach several of the same pharmaceutically acceptable components. Finally, it would have been prima facie obvious to combine the invention of Levine et al., CN102935226, Ali and Ella to advantageously achieve an immunogenic composition against pathogenic S. enterica serovars Typhi and Paratyphi known to cause typhoid infections/fevers.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". It is well known to take an immunogenic composition, where there is no change in the respective function of the conjugates, thus the combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Therefore, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Response to Arguments
8. Applicant’s arguments, filed March 13, 2026 with respect to the rejections of claims 130-136 and 154-155 under 35 U.S.C. 103 as being unpatentable over Ella et al., in view of Konadu et al., and claims 137-138 as being unpatentable over Ella et al., in view of Konadu et al. and further in view of Levine et al., have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of CN102935226 (published 2013-02-20; priority to 2012-11-16) in view of Ali et al., (Hum Vaccin Immunother. 2014;10(6):1494-8. Epub 2014 Mar 6).
Applicants argue that Ella teaches the instantly claimed Vi-TT conjugate and Ella “broadly speaks of OSP”. In response, the Office sets forth CN102935226 which specifically teach an immunogenic composition comprising: a) 1.25 mg to 50mg of a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) 1.25 mg to 50mg of a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) toxoid carrier conjugate antigen wherein the carrier is derivatized with an adipic acid dihydrazide (ADH) linker before conjugation with the Salmonella enterica serovar paratyphi A OSP polysaccharide. Therefore, CN102935226 specifically and clearly teaches the combination.
Applicants argue that Konadu, like CN102935226 teach OSP-ADH linked to tetanus. However Ali et al., specifically teach OSP-ADH-DT conjugation. Additionally, no more than routine skill is required to incorporate the conjugate of Ali et al., because the use of DT as carrier protein in developing conjugate vaccine candidates against S. Typhi has previously been reported; thus no more than routine skill is required for the well known exchange. Additionally, Ali et al., teach the OSP-DT and OSP-AH-DT conjugate permits better access to the antigen sites on the OSP in the conjugate with the spacer and/or allow for higher free polysaccharide content in the conjugate. Ali et al., teach various conjugation strategies have been reported including recent conjugation chemistry to link the S. Paratyphi A O:2 and the carrier protein CRM197. These conjugates were found to have bactericidal activity against S. Paratyphi A [Discussion].
Moreover, Ali et al., provides additional motivation to exchange the tetanus for diphtheria. Ali states S. Paratyphi A OSP was bound to tetanus toxoid (TT) with and without ADH linker, and the conjugate with the linker was more immunogenic than the conjugate without the linker. However, that conjugate did not elicit a booster response in young children. This was in contrast to the booster response elicited in this age group by pneumococcus type 6B-TT, Vi-rEPA, and Shigella flexneri 2a-rEPA conjugate [Discussion].
Therefore, Ali et al., clearly teach one of ordinary skill would be motivated to exchange the TT for DT because Ali’s results demonstrated that OSP purified from S. Paratyphi A can be conjugated to DT carrier protein and the enhanced immune response seen with the OSP-AH-DT conjugate is indicative of a successful conjugation.
Declaration of S. S. Pisal under 37 CFR 1.132
The declaration of S. S. Pisal. under 37 CFR 1.132 filed March 11, 2026 is insufficient to overcome the new rejection of claims 130-132, 135-138, 144 and 154-155. Point 1 of the declaration is drawn to the OSP-ADH-DT conjugate. However the conjugate of Ali teach the instantly recited conjugate. Applicants are remined that the product by process claims are not limited to the manipulation of the recite steps, only the structure implied by the steps. Applicants have not pointed to any structural differences between the conjugates wherein the DT is derivatized with an adipic acid dihydrazide (ADH) linker before conjugation with the Salmonella enterica serovar paratyphi A OSP polysaccharide and conjugates where the OSP is linked to the ADH and then DT. At best, the Declaration pointed out the OSP is at risk for structural degradation and decreased immunogenic response, which do not further limit the structural presentation of the conjugate. Furthermore, Ali et al., specifically teach structural integrity and increased immunogenic response. Therefore, the Declaration does not overcome the teaching of Ali et al.
Next the Declaration addresses point 2 which is drawn to the combination of Vi-TT and OSP-DT produces the highest immunogenicity response in mice. CN102935226 teach an immunogenic composition comprising: a) 1.25 mg to 50mg of a Salmonella enterica serovar typhi Vi polysaccharide-tetanus toxoid (TT) conjugate antigen; and b) 1.25 mg to 50mg of a Salmonella enterica serovar paratyphi A O-specific polysaccharide (OSP) toxoid carrier conjugate antigen wherein the carrier is derivatized with an adipic acid dihydrazide (ADH) linker before conjugation with the Salmonella enterica serovar paratyphi A OSP polysaccharide. Ali et al., teach the carrier toxoid for Salmonella enterica serovar paratyphi A OSP polysaccharide is diphtheria. However, CN102935226 teaches immunogenicity responses in mice. Both Ali et al., and Ella et al., teach production immunogenicity responses.
Finally, the Declaration addresses point 3 which is drawn to the immunogenic response is reproducible in other animal models. However, the instant claims do not require any immune response in any animal model. Furthermore, CN102935226 and Ella both teaches dosages within the claimed range.
Therefore, the Declaration does not overcome the rejection of claims 130-132, 135-136, 144 and 154-155 are rejected under 35 U.S.C. 103 as being unpatentable over CN102935226 in view of Ali et al., and Ella et al.
Pertinent Art
9. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Micoli et al., WO2009150543 published 2009-12-17; priority to 2008-06-13).
Micoli et al., teach a composition may comprise a Vi conjugate of the invention in combination with a Salmonella paratyphi A antigen, such as an H or O antigen (e.g. an 0:2 saccharide antigen), to provide a bivalent typhoid vaccine [para 158]. Micoli et al., teach conjugates have been prepared by carbodiimide-mediated synthesis, using adipic acid dihydrazide derivatized CRM197 (a non-toxic variant of diphtheria toxin) and tetanus toxoid, as carrier proteins [abstract]. Micoli et al., teach a linker, such as adipic acid dihydrazide (ADH), and a carbodiimide, such as 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDAC), are simultaneously added to a solution containing a carrier protein, such as CRM197 or tetanus toxoid (TT), to give a derivatised carrier protein [para 6].
Ramasamy et al., (WO2015029056 published 2015-03-05)
Ramasamy et al., teach stable conjugate vaccine formulations for protection against Salmonella typhi, and methods of conjugation between Vi-polysaccharide of S. typhi to tetanus toxoid as the carrier protein, responsible for producing improved T-dependent immune response against Typhoid fever caused by Salmonella typhi [abstract]. The agents that cause enteric fever are therefore Salmonella enterica subspecies enterica serovar typhi (commonly referred to as S. enterica serovar typhi) and serovars Paratyphi A, B and C. A serovar or serotype can be defined as a strain that has a unique surface molecule which is responsible for the production of specific antibody [para 3]. The prior art discloses an isolated lipo-polysaccharide from Salmonella Paratyphi A, having removed its Lipid A through detoxification and retaining its O-acetyl content between 70% to 80% and then conjugated to a carrier protein tetanus toxoid through adipic acid dihydrazide (ADH) [para 6. Ramasamy et al., teach producing typhoid conjugate vaccines is therefore, specific to the particular carrier protein involved and the native polysaccharide involved in the conjugation process and the resulting conjugate vaccine. Each carrier protein-polysaccharide conjugation makes itself a different identity of conjugate vaccine [para 9]. Hence, there exists a need of alternating conjugation methodologies, which would reduce costs, and the number of injections to only one injection capable of eliciting sufficient immune response and other associated technical concerns in the field of conjugation chemistry which would be more simpler, less time consuming, cost-effective and safe. An efficient vaccine must be capable of triggering a good immune response and must be applicable for use in infants especially below 2 years of age. The disclosure as set forth in this invention attributes to novel alternative methods of conjugating the Vi-polysaccharide along with the specific carrier protein tetanus toxoid (TT) in an inventive manner put-forth in this application which potentially overcomes the drawbacks of native polysaccharide vaccines and also current conjugation methodologies including other ViPs vaccines conjugated to carrier proteins [para 11]. Alternatively CRM197 and/or TT were derivatized with treatment with ADH and EDAC. Vi was conjugated to CRM197 and TT separately and the conjugation mixture was purified using Sephacryl S-1000; fractions were analysed by SDS-PAGE and those which did not contain free protein were collected (Micoli et al., 2011).
A linker molecule for example ADH, contains terminal amine groups at both the ends. The Vi native polysaccharide which is further reduced in its size prior to conjugation, contains abundant functional carboxyl groups (—COOH) naturally. Carrier proteins for example, tetanus toxoid contain both the amine (—NH2) and the carboxyl groups (—COOH). In case of conjugation of the ViPs to the carrier protein with the help of a linker molecule ADH, is effected in presence of cross linking agents such as EDAC, wherein the —COOH group of the ViPs should bind with the one —NH2 group of the ADH linker through one of its ends. The activated ViPs is coupled with the linker ADH, connected through a —CONH bond at one end of the ADH molecule. The other end of the ADH molecule remains free to be further bond with the —COOH group present in the carrier proteins at appropriate concentrations and temperature ranges. The activated ViPs-ADH is therefore again reacted with the carrier protein in presence of cross linking agent EDAC, which enables the —NH2 present at the other end of the ADH molecule to bind with the —COOH group of the carrier protein molecule, thereby forming an effective bridge between the Vi-polysaccharide and the carrier protein. Thus in this method, there is a necessity remove excess linkers, after treating ViPs with ADH, and again after treating ViPs-ADH to carrier protein. Further EDAC is required to use twice in this method [para 92].
Saul et al., (US20140329998) teach methods for making saccharide-protein glycoconjugates. Saul et al., teach conjugating the O-antigen-core from S. Paratyphi to CRM197. Methods C and D: Activation of the terminal KDO with ADH (Method or CDH (Method D) by reductive amination and conjugation with CRM197 via SIDEA linker O-antigen-core derivatization with ADH or CDH at KDO by reductive amination.
WO2009/150543 describes a conjugated Vi-polysaccharide to be used as a vaccine composition against Salmonella typhi causing typhoid fever, wherein the Vi-polysaccharide is covalently conjugated to a protein selected from CRM197 or tetanus toxoid. The method of conjugation as disclosed in WO2009/150543 includes first simultaneously adding carrier protein which is preferably CRM197 or tetanus toxoid to a linker such as adipic acid -dihydrazide (ADH), and a carbodiimide such as l-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDAC), to give a derivatized carrier protein in presence of a 2-(N-morpholino) ethane sulphonic acid (MES buffer). The derivatized carrier protein CRM197 or tetanus toxoid and the activated Vi-polysaccharide of Salmonella typhi is then reacted with each other to get the conjugated ViPs-CRM197 or ViPs-TT conjugate, followed by removal of the excess linker.
However, according to WO2009/150543, the excess linker has been removed by dialysis, whereas in the present invention, Vi-polysaccharide was optionally subjected for size reduction (homogenization or by microwave method) and then conjugation has been achieved optionally coupled to the linker molecule or without any linker molecule at all.
Conclusion
10. No claims allowed.
11. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/JANA A HINES/Primary Examiner, Art Unit 1645
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